Background Arteriovenous fistulas (AVF) for haemodialysis often experience early thrombosis and m... more Background Arteriovenous fistulas (AVF) for haemodialysis often experience early thrombosis and maturation failure requiring intervention and/or central venous catheter (CVC) placement. This secondary and exploratory analysis of the FAVOURED study determined whether omega-3 fatty acids (fish oils) or aspirin affected AVF usability, intervention rates and CVC requirements. Methods In 567 adult participants planned for AVF creation, all were randomised to fish oil (4g/d) or placebo, and 406 to aspirin (100mg/d) or placebo, starting one day pre-surgery and continued for three months. Outcomes evaluated within 12 months included AVF intervention rates, CVC exposure, late dialysis suitability failure, and times to primary patency loss, abandonment and successful cannulation.
Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. TGF-β1/Smad3 signalli... more Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. TGF-β1/Smad3 signalling plays a major pathological role in DN; however, the contribution of Smad4 has not been examined. Knock-down of Smad4 expression in the kidney using an anti-Smad4 locked nucleic acid halted progressive podocyte damage and glomerulosclerosis in mouse type 2 DN, suggesting a pathogenic role of Smad4 in podocytes. We identified up-regulation of Smad4 in podocytes in human and mouse DN. Next, conditional Smad4 deletion in podocytes was shown to protected mice from type 2 DN independent of obesity. Mechanistically, hyperglycaemia induces Smad4 localisation to mitochondria in podocytes resulting in reduced glycolysis and oxidative phosphorylation, and increased production of reactive oxygen species. This operates, in part, via direct binding of Smad4 to the glycolytic enzyme PKM2 to reduce the active tetrameric form of PKM2. In addition, Smad4 interacts with ATPIF1, causing a reduction in ATPIF1 degradation. In conclusion, we have identified a novel mitochondrial-based mechanism by which Smad4 causes diabetic podocyte injury.
Background: Haemodialysis (HD) is critically dependent on the availability of adequate access to ... more Background: Haemodialysis (HD) is critically dependent on the availability of adequate access to the systemic circulation, ideally via a native arteriovenous fistula (AVF). The Primary failure rate of an AVF ranges between 20-54%, due to thrombosis or failure of maturation. There remains limited evidence for the use of anti-platelet agents and uncertainty as to choice of agent(s) for the prevention of AVF thrombosis. We present the study protocol for a randomised, double-blind, placebo-controlled, clinical trial examining whether the use of the anti-platelet agents, aspirin and omega-3 fatty acids, either alone or in combination, will effectively reduce the risk of early thrombosis in de novo AVF. Methods/Design: The study population is adult patients with stage IV or V chronic kidney disease (CKD) currently on HD or where HD is planned to start within 6 months in whom a planned upper or lower arm AVF is to be the primary HD access. Using a factorial-design trial, patients will be randomised to aspirin or matching placebo, and also to omega-3 fatty acids or matching placebo, resulting in four treatment groups (aspirin placebo/omega-3 fatty acid placebo, aspirin/omega-3 fatty acid placebo, aspirin placebo/omega-3 fatty acid, aspirin/omega-3 fatty acid). Randomisation will be achieved using a dynamic balancing method over the two stratification factors of study site and upper versus lower arm AVF. The medication will be commenced pre-operatively and continued for 3 months post surgery. The primary outcome is patency of the AVF at three months
Background. Clinical practice guidelines recommend that the preferred method of surveillance for ... more Background. Clinical practice guidelines recommend that the preferred method of surveillance for arteriovenous fistula (AVF) is the measurement of AVF blood flow (Qa). As these recommendations are based on observational studies, we conducted a randomized, prospective, double-blind, controlled trial to assess whether Qa surveillance results in an increased detection of AVF stenosis. Methods. A total of 137 patients were randomly assigned to receive either continuing AVF surveillance using current clinical criteria (control, usual treatment) or usual treatment plus AVF blood-flow surveillance by ultrasound dilution (Qa surveillance group). The primary outcome measure was the detection of a significant (>50%) AVF stenosis. Results. There were 67 and 68 patients assigned to the control and Qa surveillance groups, respectively. Patients in the Qa surveillance group were twice as likely to have a stenosis detected compared with the control hazard ratio (HR) confidence interval (CI) group (2.27, 95% 0.85-5.98, P ¼ 0.09), with a trend for a significant stenosis to be detected earlier in the Qa surveillance group (P ¼ 0.09, log rank test). However, using the Qa results alone prior to angiography, the area under the receiver operating characteristic curve demonstrated, at best, a moderate prediction of (>50%) AVF stenosis (0.78, 95% CI 0.63-0.94, P ¼ 0.006). Conclusion. This study demonstrates that the addition of AVF Qa monitoring to clinical screening for AVF stenosis resulted in a non-significant doubling in the detection of angiographically significant AVF stenosis. Further, large multi-centre randomized trials are feasible and will be necessary to confirm whether Qa surveillance and the correction of detected AVF stenosis will lead to a reduction in AVF thrombosis and increased AVF survival.
Darbepoetin alfa (Aranesp@, Amgen Ltd) is a long-acting, hyperglycosylated recombinant human eryt... more Darbepoetin alfa (Aranesp@, Amgen Ltd) is a long-acting, hyperglycosylated recombinant human erythropoietin (r-HuEPO; epoetin) analogue, developed for the treatment of anaemia in patients with chronic kidney disease (CKD, i.e. end-stage renal failure or progressive renal impairment). Based on previously published European guidelines, this review article presents key recommendations for the use of darbepoetin alfa in Australasian clinical practice. Darbepoetin alfa is expected to be a valuable alternative therapeutic agent for the management of renal anaemia. Clinical data demonstrate that: Once-weekly administration of darbepoetin alfawhether by subcutaneous (s.c.) or intravenous (i.v.) injectionis as effective as epoetin therapy, administered two or three times per week; patients receiving once-weekly doses of epoetin can be switched to darbepoetin alfa, once every 2 weeks; target haemoglobin (Hb) concentrations can be successfully maintained in patients switched from epoetin therapy to less frequently administered doses of darbepoetin alfa (administration once every 2 weeks is sufficient for some patients); and darbepoetin alfa has a similar safety profile to epoetin. In addition to addressing a number of practical considerations relating to the use of darbepoetin alfa in clinical practice, this article also highlights principal findings from several key clinical studies.
Changes in body composition and its relation to muscle strength in 75-year-old men and women: a 5... more Changes in body composition and its relation to muscle strength in 75-year-old men and women: a 5-year prospective follow-up study of the NORA cohort in Goteborg,
Background: Serum fibroblast growth factor 23 (FGF-23) levels are markedly elevated in haemodialy... more Background: Serum fibroblast growth factor 23 (FGF-23) levels are markedly elevated in haemodialysis patients and have been linked to mortality outcomes. Small studies in health and chronic kidney disease, have demonstrated marked intra-and inter-individual variability in measured FGF-23 levels, and variable degradation in serum as compared to plasma samples. In end-stage kidney disease (ESKD), the intra-and inter-individual variability of FGF-23 levels, and the optimal collection methods remain poorly characterized. In this study we assessed the variability of FGF-23 levels in a cohort of stable haemodialysis patients. Secondly, in a subset of patients, we assessed the effects of different collection methods on measured FGF-23 levels. Methods: To assess the variability of FGF-23, pre-dialysis blood samples were collected over 3 consecutive weeks from 75 haemodialysis patients. The effects of different specimen collection methods were examined in a subset of patients (n = 23), with pre-dialysis blood collected into different tubes: plain (serum), EDTA (plasma) and EDTA with the addition of a protease inhibitor (EDTA-PI). All analyses were performed in the main cohort and repeated in each subgroup. Variability over a 3-week period was assessed using repeated measures ANOVA and random effects linear regression models. Intra-class correlation coefficients were calculated to assess agreement, and coefficients of variation were calculated to assess intra-and inter-individual variability. Results: Over the 3-week study period the mean FGF-23 levels were not significantly different in the serum (p = 0. 26), EDTA (p = 0.62) and EDTA-PI (p = 0.55) groups. FGF-23 levels demonstrated marked intra-and inter-individual variability with a CV of 36 and 203.2%, respectively. In the subgroup analysis, the mean serum FGF-23 levels were significantly lower than the EDTA (p < 0.001) or EDTA-PI (p < 0.001) groups, however there was no difference in mean FGF-23 levels between EDTA and EDTA-PI (p = 0.54). Conclusions: The measured FGF-23 levels were significantly lower in serum as compared to plasma, and the addition of a protease inhibitor did not confer an additional benefit. Importantly in this cohort of ESKD patients, FGF-23 levels showed marked intra-and inter-individual variability. The routine measurement of FGF-23 in ESKD remains challenging, however this study suggests the plasma is the optimal collection method for FGF-23 analysis.
hronic kidney disease (CKD) is a significant and growing public health problem that is responsibl... more hronic kidney disease (CKD) is a significant and growing public health problem that is responsible for a substantial burden of illness and premature mortality. A recent Australian estimate has suggested that about one in three adult Australians is at increased risk of developing CKD and that one in seven has at least one clinical sign of existing CKD. 1 The incidence and prevalence of both CKD and the management of end-stage kidney disease (ESKD) by dialysis and transplantation have been increasing over the past 40 years (Box 1). 2 At the end of 2008, more than 17 500 Australians were receiving some form of renal replacement therapy (renal transplantation or dialysis), and 10 000 of these were undergoing dialysis. 2 This growth is attributed primarily to two factors: an ageing population and the increasing prevalence of type 2 diabetes. Comprehensive costing of the economic burden of dialysis in Australia (in 2004 dollars) indicates that the annual health care cost of ESKD in 2010 will be between $800 million and $900 million. 3 This represents an increase of about 50% from 2004. Moreover, there are other indirect physical, psychosocial, and economic costs, which can result in significant financial, vocational, educational, and emotional pressures for individuals, their families and the wider community.
Background BK virus associated nephropathy (BKVN) is an important cause of early graft dysfunctio... more Background BK virus associated nephropathy (BKVN) is an important cause of early graft dysfunction in renal transplant recipients. The present study was carried out to determine the burden of BKVN in a single renal transplant centre in Australia. Method A retrospective analysis of de novo renal transplant recipients from 2010 to 2013 was performed to identify biopsy proven BKVN. Estimated glomerular filtration rate (eGFR) was compared at baseline, at BKVN diagnosis and 3 and 12 months postdiagnosis. Result Of the 317 de novo renal transplants recipients in the study period, 20 (6.3%) developed BKVN. The mean age was 54.8 ± 13.1 years and 13 (65%) were male. The mean time from transplant to BKVN was 8.7 ± 6.7 months with 17 (85%) diagnosed within 12 months. Four recipients each were diagnosed BKVN on 3 and 12 month surveillance biopsy. Six (30%) had normal eGFR at diagnosis. Mean eGFR at diagnosis was 38.8 ± 19.2 ml/min/1.73 m 2 , which was significantly lower (p < 0.01) than that at baseline (50.3 ± 16.4 ml/min/1.73 m 2). eGFR improved numerically at 3 and 12 months post-diagnosis, however the difference was not significant. One patient had graft failure, 19 months after diagnosis. Conclusion BKVN generally occurs in first post-transplant year and is an important cause of early graft dysfunction. Surveillance biopsy helps in detecting subclinical BKVN.
Background: Patients with diabetes and chronic kidney disease (CKD) are a complex subset of the g... more Background: Patients with diabetes and chronic kidney disease (CKD) are a complex subset of the growing number of patients with diabetes, due to multi-morbidity. Gaps between recommended and received care for diabetes and chronic kidney disease (CKD) are evident despite promulgation of guidelines. Here, we document gaps in tertiary health-care, and the commonest patient-reported barriers to health-care, before exploring the association between these gaps and barriers. Methods: This cross-sectional study recruited patients with diabetes and CKD (eGFR < 60 mL/min/1.73 m 2) across 4 large hospitals. For each patient, questionnaires were completed examining clinical data, recommended care, and patient-reported barriers limiting health-care. Descriptive statistics, subgroup analyses by CKD stage and hospital, and analyses examining the relationship between health-care gaps and barriers were performed. Results: 308 patients, of mean age 66.9 (SD 11.0) years, and mostly male (69.5%) and having type 2 diabetes (88.0%), participated. 49.1% had stage 3, 24.7% stage 4 and 26.3% stage 5 CKD. Gaps between recommended versus received care were evident: 31.9% of patients had an HbA1c ≥ 8%, and 39.3% had a measured blood pressure ≥ 140/90 mmHg. The commonest barriers were poor continuity of care (49.3%), inadequate understanding/education about CKD (43.5%) , and feeling unwell (42.6%). However, barriers associated with a failure to receive items of recommended care were inadequate support from family and friends, conflicting advice from and poor communication amongst specialists, the effect of co-morbidities on self-management and feeling unmotivated (all p < 0.05). Conclusions: Barriers to health-care varied across CKD stages and hospitals. Barriers associated with a deviation from recommended care were different for different items of care, suggesting that specific interventions targeting each item of care are required.
Background. Although clinical guidelines exist for optimal levels of serum markers of chronic kid... more Background. Although clinical guidelines exist for optimal levels of serum markers of chronic kidney disease mineral and bone disorder (CKD-MBD), target parameters are not achieved in many haemodialysis (HD) patients. The reason for this evidence-practice gap is unclear and more information from patients and healthcare professionals is required to improve knowledge transfer. We aimed to determine potential barriers by surveying HD patients and staff about awareness and management of CKD-MBD. Methods. A total of 136 prevalent HD patients, 25 nephrologists and 58 dialysis nurses/technicians were surveyed. Three separate questionnaires included issues of knowledge and awareness of CKD-MBD and factors limiting management (including compliance, medications and general understanding). Results. Of patients surveyed, 84% had heard of phosphate, but 42% were unsure of high phosphate foods and 46% unaware of consequences of elevated phosphate. Twenty-seven percent and thirty-five percent of patients, respectively, had difficulty taking or forgetting to take phosphate binders. Seventy-four percent of patients wanted to know more about CKD-MBD (40% via written material). Of nephrologists surveyed, 76% thought noncompliance with phosphate binders was the main reason for poor control of phosphate (predominantly related to poor patient understanding); 84% thought patients wanted to know more but only 28% provided written material on CKD-MBD. Of dialysis staff surveyed, 63% thought noncompliance with binders explained poor control, the main reason being lack of patient understanding; 88% thought patients wanted to know more but only 17% provided written education. Conclusions. Implementation of an intensive educational programme, with a multi-faceted approach, for HD patients may promote better control of CKD-MBD and improve achievement of target levels.
Among 24,525 patients, total patient years of follow-up were 42,174, number of deaths was 5849, a... more Among 24,525 patients, total patient years of follow-up were 42,174, number of deaths was 5849, and mortality rate was 0.14 per year. Distributions of predialysis BP and patient characteristics by predialysis SBP
BackgroundAn autologous arteriovenous fistula (AVF) is the preferred hemodialysis vascular access... more BackgroundAn autologous arteriovenous fistula (AVF) is the preferred hemodialysis vascular access, but successful creation is hampered by high rates of AVF failure. This study aimed to evaluate patient and surgical factors associated with AVF failure to improve vascular access selection and outcomes.MethodsThis is apost hocanalysis of all participants of FAVOURED, a multicenter, double-blind, multinational, randomized, placebo-controlled trial evaluating the effect of fish oil and/or aspirin in preventing AVF failure in patients receiving hemodialysis. The primary outcome of AVF failure was a composite of fistula thrombosis and/or abandonment and/or cannulation failure at 12 months post-AVF creation, and secondary outcomes included individual outcome components. Patient data (demographics, comorbidities, medications, and laboratory data) and surgical factors (surgical expertise, anesthetic, intraoperative heparin use) were examined using multivariable logistic regression analyses to...
Background: Chronic kidney disease is a significant contributor to mortality and morbidity worldw... more Background: Chronic kidney disease is a significant contributor to mortality and morbidity worldwide, and the number of people who require dialysis or transplantation continues to increase. People on dialysis are 15 times more likely to die than the general population. Dialysis is also costly, intrusive, and time-consuming and imposes an enormous burden on patients and their families. This escalating problem has spurred a proliferation of trials in dialysis, yet health and quality of life remain poor. The reasons for this are complex and varied but are attributable in part to problems in the design and reporting of studies, particularly outcome selection. Problems related to outcomes include use of unvalidated surrogates, outcomes of little or no relevance to patients, highly variable outcome selection limiting comparability across studies, and bias in reporting outcomes. The aim of the Standardised Outcomes in Nephrology-Haemodialysis (SONG-HD) study is to establish a core outcome set for haemodialysis trials, to improve the quality of reporting, and the relevance of trials conducted in people on haemodialysis. Methods/design: SONG-HD is a five-phase project that includes the following: a systematic review to identify outcomes that have been reported in haemodialysis systematic reviews and trials; nominal group technique with patients and caregivers to identify, rank, and describe reasons for their choices; qualitative stakeholder interviews with patients, caregivers, clinicians, researchers, and policy makers to elicit individual values and perspectives on outcomes for haemodialysis trials; a three-round Delphi survey with stakeholder groups to distil and generate a prioritised list of core outcomes; and a consensus workshop to establish a core outcome set for haemodialysis trials.
is the most common form of kidney replacement therapy. This study aimed to examine the use, avail... more is the most common form of kidney replacement therapy. This study aimed to examine the use, availability, accessibility, affordability, and quality of HD care worldwide.
Objective To determine the global capacity (availability, accessibility, quality, and affordabili... more Objective To determine the global capacity (availability, accessibility, quality, and affordability) to deliver kidney replacement therapy (dialysis and transplantation) and conservative kidney management. Design International cross sectional survey. Setting International Society of Nephrology (ISN) survey of 182 countries from July to September 2018. Participants Key stakeholders identified by ISN’s national and regional leaders. Main outcome measures Markers of national capacity to deliver core components of kidney replacement therapy and conservative kidney management. Results Responses were received from 160 (87.9%) of 182 countries, comprising 97.8% (7338.5 million of 7501.3 million) of the world’s population. A wide variation was found in capacity and structures for kidney replacement therapy and conservative kidney management—namely, funding mechanisms, health workforce, service delivery, and available technologies. Information on the prevalence of treated end stage kidney di...
American journal of kidney diseases : the official journal of the National Kidney Foundation, Jan 3, 2016
Evidence-informed decision making in clinical care and policy in nephrology is undermined by tria... more Evidence-informed decision making in clinical care and policy in nephrology is undermined by trials that selectively report a large number of heterogeneous outcomes, many of which are not patient centered. The Standardized Outcomes in Nephrology-Hemodialysis (SONG-HD) Initiative convened an international consensus workshop on November 7, 2015, to discuss the identification and implementation of a potential core outcome set for all trials in hemodialysis. The purpose of this article is to report qualitative analyses of the workshop discussions, describing the key aspects to consider when establishing core outcomes in trials involving patients on hemodialysis therapy. Key stakeholders including 8 patients/caregivers and 47 health professionals (nephrologists, policymakers, industry, and researchers) attended the workshop. Attendees suggested that identifying core outcomes required equitable stakeholder engagement to ensure relevance across patient populations, flexibility to consider ...
Introduction Background. It has been estimated that 30-50% of adult haemodialysis patients have m... more Introduction Background. It has been estimated that 30-50% of adult haemodialysis patients have moderate to severe Chronic dialysis is an established treatment for patients malnutrition. We have previously shown that estimawith end stage renal disease. The number of new tion of total body nitrogen, expressed as a nitrogen dialysis patients is increasing world wide. However, index (NI) by in vivo neutron activation analysis the life-expectancy of these patients is still lower than (IVNAA) is an accurate tool for estimating total body that of the general population [1]. Dialysis patients protein in dialysis patients. It is not clear whether the have an age-adjusted death ratio that is estimated to nitrogen index is predictive of mortality and morbidity be 4-5 times more than that of the general population. in dialysis patients. A considerable proportion of this high mortality in Methods. We studied the long-term predictive value of these patients can be explained by a high prevalence nutritional assessment by IVNAA and serum albumin of non-renal comorbid conditions such as diabetes on mortality and morbidity (including infection epismellitus and cardiovascular disease [2]. In recent years odes requiring hospital admission, ischaemic heart there has been a growing realization that malnutrition disease (IHD), cerebrovascular or peripheral vascular in dialysis patients may be associated with poor outdisease (PVD). Seventy-six chronic haemodialysis come. Most studies agree that the effect of malnutrition patients were initially studied between 1989 and 1991, on morbidity and mortality in dialysis patients is with a minimum follow-up of 5 years. The mean age substantial. However, most of these studies are retroof the patients was 48.3 years (range 21-76). Patients spective and cross-sectional with limited long-term were divided into two groups, group I, n=22, had a follow up [3,4]. Moreover, traditional methods of NI∏0.8 (NI∏0.8 represents protein malnutrition) and nutritional assessment lack reproducibility and are group II, n=54, had a NI>0.8. prone to patient and observer error. We have shown Results. Fifteen patients in group II died in the followpreviously that anthropometry underestimates body up period compared to nine from group I (P<0.05), protein in haemodialysis patients and in vivo neutron but NI∏0.8 did not predict vascular or infective moractivation analysis (IVNAA) of total body nitrogen bidity. Serum albumin∏35 g/day did predict over all (TBN) is more accurate in the estimation of the mortality (P<0.05) as well as infection episodes nutritional state [5]. This study was designed to assess (P<0.001). When patients above the age of 50 years the predictive value of serum albumin, and total body were analysed, NI did predict mortality (P<0.05) but nitrogen by IVNAA on the long-term morbidity and serum albumin did not, while the age of>50 itself was mortality in haemodialysis patients. a strong predictor of mortality (P<0.001). Conclusion. We conclude that NI∏0.8 is predictive of long-term mortality. This reinforces the view that low body protein stores are predictive of increased mortal-Subjects and methods ity in dialysis patients and that the serum albumin is predictive of mortality because of its reflection of The study was approved by the Human Ethics Committee protein stores. of Monash Medical Centre. Ninety-one patients on haemodialysis between 1989 and 1991 under the supervision of
Background Arteriovenous fistulas (AVF) for haemodialysis often experience early thrombosis and m... more Background Arteriovenous fistulas (AVF) for haemodialysis often experience early thrombosis and maturation failure requiring intervention and/or central venous catheter (CVC) placement. This secondary and exploratory analysis of the FAVOURED study determined whether omega-3 fatty acids (fish oils) or aspirin affected AVF usability, intervention rates and CVC requirements. Methods In 567 adult participants planned for AVF creation, all were randomised to fish oil (4g/d) or placebo, and 406 to aspirin (100mg/d) or placebo, starting one day pre-surgery and continued for three months. Outcomes evaluated within 12 months included AVF intervention rates, CVC exposure, late dialysis suitability failure, and times to primary patency loss, abandonment and successful cannulation.
Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. TGF-β1/Smad3 signalli... more Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. TGF-β1/Smad3 signalling plays a major pathological role in DN; however, the contribution of Smad4 has not been examined. Knock-down of Smad4 expression in the kidney using an anti-Smad4 locked nucleic acid halted progressive podocyte damage and glomerulosclerosis in mouse type 2 DN, suggesting a pathogenic role of Smad4 in podocytes. We identified up-regulation of Smad4 in podocytes in human and mouse DN. Next, conditional Smad4 deletion in podocytes was shown to protected mice from type 2 DN independent of obesity. Mechanistically, hyperglycaemia induces Smad4 localisation to mitochondria in podocytes resulting in reduced glycolysis and oxidative phosphorylation, and increased production of reactive oxygen species. This operates, in part, via direct binding of Smad4 to the glycolytic enzyme PKM2 to reduce the active tetrameric form of PKM2. In addition, Smad4 interacts with ATPIF1, causing a reduction in ATPIF1 degradation. In conclusion, we have identified a novel mitochondrial-based mechanism by which Smad4 causes diabetic podocyte injury.
Background: Haemodialysis (HD) is critically dependent on the availability of adequate access to ... more Background: Haemodialysis (HD) is critically dependent on the availability of adequate access to the systemic circulation, ideally via a native arteriovenous fistula (AVF). The Primary failure rate of an AVF ranges between 20-54%, due to thrombosis or failure of maturation. There remains limited evidence for the use of anti-platelet agents and uncertainty as to choice of agent(s) for the prevention of AVF thrombosis. We present the study protocol for a randomised, double-blind, placebo-controlled, clinical trial examining whether the use of the anti-platelet agents, aspirin and omega-3 fatty acids, either alone or in combination, will effectively reduce the risk of early thrombosis in de novo AVF. Methods/Design: The study population is adult patients with stage IV or V chronic kidney disease (CKD) currently on HD or where HD is planned to start within 6 months in whom a planned upper or lower arm AVF is to be the primary HD access. Using a factorial-design trial, patients will be randomised to aspirin or matching placebo, and also to omega-3 fatty acids or matching placebo, resulting in four treatment groups (aspirin placebo/omega-3 fatty acid placebo, aspirin/omega-3 fatty acid placebo, aspirin placebo/omega-3 fatty acid, aspirin/omega-3 fatty acid). Randomisation will be achieved using a dynamic balancing method over the two stratification factors of study site and upper versus lower arm AVF. The medication will be commenced pre-operatively and continued for 3 months post surgery. The primary outcome is patency of the AVF at three months
Background. Clinical practice guidelines recommend that the preferred method of surveillance for ... more Background. Clinical practice guidelines recommend that the preferred method of surveillance for arteriovenous fistula (AVF) is the measurement of AVF blood flow (Qa). As these recommendations are based on observational studies, we conducted a randomized, prospective, double-blind, controlled trial to assess whether Qa surveillance results in an increased detection of AVF stenosis. Methods. A total of 137 patients were randomly assigned to receive either continuing AVF surveillance using current clinical criteria (control, usual treatment) or usual treatment plus AVF blood-flow surveillance by ultrasound dilution (Qa surveillance group). The primary outcome measure was the detection of a significant (>50%) AVF stenosis. Results. There were 67 and 68 patients assigned to the control and Qa surveillance groups, respectively. Patients in the Qa surveillance group were twice as likely to have a stenosis detected compared with the control hazard ratio (HR) confidence interval (CI) group (2.27, 95% 0.85-5.98, P ¼ 0.09), with a trend for a significant stenosis to be detected earlier in the Qa surveillance group (P ¼ 0.09, log rank test). However, using the Qa results alone prior to angiography, the area under the receiver operating characteristic curve demonstrated, at best, a moderate prediction of (>50%) AVF stenosis (0.78, 95% CI 0.63-0.94, P ¼ 0.006). Conclusion. This study demonstrates that the addition of AVF Qa monitoring to clinical screening for AVF stenosis resulted in a non-significant doubling in the detection of angiographically significant AVF stenosis. Further, large multi-centre randomized trials are feasible and will be necessary to confirm whether Qa surveillance and the correction of detected AVF stenosis will lead to a reduction in AVF thrombosis and increased AVF survival.
Darbepoetin alfa (Aranesp@, Amgen Ltd) is a long-acting, hyperglycosylated recombinant human eryt... more Darbepoetin alfa (Aranesp@, Amgen Ltd) is a long-acting, hyperglycosylated recombinant human erythropoietin (r-HuEPO; epoetin) analogue, developed for the treatment of anaemia in patients with chronic kidney disease (CKD, i.e. end-stage renal failure or progressive renal impairment). Based on previously published European guidelines, this review article presents key recommendations for the use of darbepoetin alfa in Australasian clinical practice. Darbepoetin alfa is expected to be a valuable alternative therapeutic agent for the management of renal anaemia. Clinical data demonstrate that: Once-weekly administration of darbepoetin alfawhether by subcutaneous (s.c.) or intravenous (i.v.) injectionis as effective as epoetin therapy, administered two or three times per week; patients receiving once-weekly doses of epoetin can be switched to darbepoetin alfa, once every 2 weeks; target haemoglobin (Hb) concentrations can be successfully maintained in patients switched from epoetin therapy to less frequently administered doses of darbepoetin alfa (administration once every 2 weeks is sufficient for some patients); and darbepoetin alfa has a similar safety profile to epoetin. In addition to addressing a number of practical considerations relating to the use of darbepoetin alfa in clinical practice, this article also highlights principal findings from several key clinical studies.
Changes in body composition and its relation to muscle strength in 75-year-old men and women: a 5... more Changes in body composition and its relation to muscle strength in 75-year-old men and women: a 5-year prospective follow-up study of the NORA cohort in Goteborg,
Background: Serum fibroblast growth factor 23 (FGF-23) levels are markedly elevated in haemodialy... more Background: Serum fibroblast growth factor 23 (FGF-23) levels are markedly elevated in haemodialysis patients and have been linked to mortality outcomes. Small studies in health and chronic kidney disease, have demonstrated marked intra-and inter-individual variability in measured FGF-23 levels, and variable degradation in serum as compared to plasma samples. In end-stage kidney disease (ESKD), the intra-and inter-individual variability of FGF-23 levels, and the optimal collection methods remain poorly characterized. In this study we assessed the variability of FGF-23 levels in a cohort of stable haemodialysis patients. Secondly, in a subset of patients, we assessed the effects of different collection methods on measured FGF-23 levels. Methods: To assess the variability of FGF-23, pre-dialysis blood samples were collected over 3 consecutive weeks from 75 haemodialysis patients. The effects of different specimen collection methods were examined in a subset of patients (n = 23), with pre-dialysis blood collected into different tubes: plain (serum), EDTA (plasma) and EDTA with the addition of a protease inhibitor (EDTA-PI). All analyses were performed in the main cohort and repeated in each subgroup. Variability over a 3-week period was assessed using repeated measures ANOVA and random effects linear regression models. Intra-class correlation coefficients were calculated to assess agreement, and coefficients of variation were calculated to assess intra-and inter-individual variability. Results: Over the 3-week study period the mean FGF-23 levels were not significantly different in the serum (p = 0. 26), EDTA (p = 0.62) and EDTA-PI (p = 0.55) groups. FGF-23 levels demonstrated marked intra-and inter-individual variability with a CV of 36 and 203.2%, respectively. In the subgroup analysis, the mean serum FGF-23 levels were significantly lower than the EDTA (p < 0.001) or EDTA-PI (p < 0.001) groups, however there was no difference in mean FGF-23 levels between EDTA and EDTA-PI (p = 0.54). Conclusions: The measured FGF-23 levels were significantly lower in serum as compared to plasma, and the addition of a protease inhibitor did not confer an additional benefit. Importantly in this cohort of ESKD patients, FGF-23 levels showed marked intra-and inter-individual variability. The routine measurement of FGF-23 in ESKD remains challenging, however this study suggests the plasma is the optimal collection method for FGF-23 analysis.
hronic kidney disease (CKD) is a significant and growing public health problem that is responsibl... more hronic kidney disease (CKD) is a significant and growing public health problem that is responsible for a substantial burden of illness and premature mortality. A recent Australian estimate has suggested that about one in three adult Australians is at increased risk of developing CKD and that one in seven has at least one clinical sign of existing CKD. 1 The incidence and prevalence of both CKD and the management of end-stage kidney disease (ESKD) by dialysis and transplantation have been increasing over the past 40 years (Box 1). 2 At the end of 2008, more than 17 500 Australians were receiving some form of renal replacement therapy (renal transplantation or dialysis), and 10 000 of these were undergoing dialysis. 2 This growth is attributed primarily to two factors: an ageing population and the increasing prevalence of type 2 diabetes. Comprehensive costing of the economic burden of dialysis in Australia (in 2004 dollars) indicates that the annual health care cost of ESKD in 2010 will be between $800 million and $900 million. 3 This represents an increase of about 50% from 2004. Moreover, there are other indirect physical, psychosocial, and economic costs, which can result in significant financial, vocational, educational, and emotional pressures for individuals, their families and the wider community.
Background BK virus associated nephropathy (BKVN) is an important cause of early graft dysfunctio... more Background BK virus associated nephropathy (BKVN) is an important cause of early graft dysfunction in renal transplant recipients. The present study was carried out to determine the burden of BKVN in a single renal transplant centre in Australia. Method A retrospective analysis of de novo renal transplant recipients from 2010 to 2013 was performed to identify biopsy proven BKVN. Estimated glomerular filtration rate (eGFR) was compared at baseline, at BKVN diagnosis and 3 and 12 months postdiagnosis. Result Of the 317 de novo renal transplants recipients in the study period, 20 (6.3%) developed BKVN. The mean age was 54.8 ± 13.1 years and 13 (65%) were male. The mean time from transplant to BKVN was 8.7 ± 6.7 months with 17 (85%) diagnosed within 12 months. Four recipients each were diagnosed BKVN on 3 and 12 month surveillance biopsy. Six (30%) had normal eGFR at diagnosis. Mean eGFR at diagnosis was 38.8 ± 19.2 ml/min/1.73 m 2 , which was significantly lower (p < 0.01) than that at baseline (50.3 ± 16.4 ml/min/1.73 m 2). eGFR improved numerically at 3 and 12 months post-diagnosis, however the difference was not significant. One patient had graft failure, 19 months after diagnosis. Conclusion BKVN generally occurs in first post-transplant year and is an important cause of early graft dysfunction. Surveillance biopsy helps in detecting subclinical BKVN.
Background: Patients with diabetes and chronic kidney disease (CKD) are a complex subset of the g... more Background: Patients with diabetes and chronic kidney disease (CKD) are a complex subset of the growing number of patients with diabetes, due to multi-morbidity. Gaps between recommended and received care for diabetes and chronic kidney disease (CKD) are evident despite promulgation of guidelines. Here, we document gaps in tertiary health-care, and the commonest patient-reported barriers to health-care, before exploring the association between these gaps and barriers. Methods: This cross-sectional study recruited patients with diabetes and CKD (eGFR < 60 mL/min/1.73 m 2) across 4 large hospitals. For each patient, questionnaires were completed examining clinical data, recommended care, and patient-reported barriers limiting health-care. Descriptive statistics, subgroup analyses by CKD stage and hospital, and analyses examining the relationship between health-care gaps and barriers were performed. Results: 308 patients, of mean age 66.9 (SD 11.0) years, and mostly male (69.5%) and having type 2 diabetes (88.0%), participated. 49.1% had stage 3, 24.7% stage 4 and 26.3% stage 5 CKD. Gaps between recommended versus received care were evident: 31.9% of patients had an HbA1c ≥ 8%, and 39.3% had a measured blood pressure ≥ 140/90 mmHg. The commonest barriers were poor continuity of care (49.3%), inadequate understanding/education about CKD (43.5%) , and feeling unwell (42.6%). However, barriers associated with a failure to receive items of recommended care were inadequate support from family and friends, conflicting advice from and poor communication amongst specialists, the effect of co-morbidities on self-management and feeling unmotivated (all p < 0.05). Conclusions: Barriers to health-care varied across CKD stages and hospitals. Barriers associated with a deviation from recommended care were different for different items of care, suggesting that specific interventions targeting each item of care are required.
Background. Although clinical guidelines exist for optimal levels of serum markers of chronic kid... more Background. Although clinical guidelines exist for optimal levels of serum markers of chronic kidney disease mineral and bone disorder (CKD-MBD), target parameters are not achieved in many haemodialysis (HD) patients. The reason for this evidence-practice gap is unclear and more information from patients and healthcare professionals is required to improve knowledge transfer. We aimed to determine potential barriers by surveying HD patients and staff about awareness and management of CKD-MBD. Methods. A total of 136 prevalent HD patients, 25 nephrologists and 58 dialysis nurses/technicians were surveyed. Three separate questionnaires included issues of knowledge and awareness of CKD-MBD and factors limiting management (including compliance, medications and general understanding). Results. Of patients surveyed, 84% had heard of phosphate, but 42% were unsure of high phosphate foods and 46% unaware of consequences of elevated phosphate. Twenty-seven percent and thirty-five percent of patients, respectively, had difficulty taking or forgetting to take phosphate binders. Seventy-four percent of patients wanted to know more about CKD-MBD (40% via written material). Of nephrologists surveyed, 76% thought noncompliance with phosphate binders was the main reason for poor control of phosphate (predominantly related to poor patient understanding); 84% thought patients wanted to know more but only 28% provided written material on CKD-MBD. Of dialysis staff surveyed, 63% thought noncompliance with binders explained poor control, the main reason being lack of patient understanding; 88% thought patients wanted to know more but only 17% provided written education. Conclusions. Implementation of an intensive educational programme, with a multi-faceted approach, for HD patients may promote better control of CKD-MBD and improve achievement of target levels.
Among 24,525 patients, total patient years of follow-up were 42,174, number of deaths was 5849, a... more Among 24,525 patients, total patient years of follow-up were 42,174, number of deaths was 5849, and mortality rate was 0.14 per year. Distributions of predialysis BP and patient characteristics by predialysis SBP
BackgroundAn autologous arteriovenous fistula (AVF) is the preferred hemodialysis vascular access... more BackgroundAn autologous arteriovenous fistula (AVF) is the preferred hemodialysis vascular access, but successful creation is hampered by high rates of AVF failure. This study aimed to evaluate patient and surgical factors associated with AVF failure to improve vascular access selection and outcomes.MethodsThis is apost hocanalysis of all participants of FAVOURED, a multicenter, double-blind, multinational, randomized, placebo-controlled trial evaluating the effect of fish oil and/or aspirin in preventing AVF failure in patients receiving hemodialysis. The primary outcome of AVF failure was a composite of fistula thrombosis and/or abandonment and/or cannulation failure at 12 months post-AVF creation, and secondary outcomes included individual outcome components. Patient data (demographics, comorbidities, medications, and laboratory data) and surgical factors (surgical expertise, anesthetic, intraoperative heparin use) were examined using multivariable logistic regression analyses to...
Background: Chronic kidney disease is a significant contributor to mortality and morbidity worldw... more Background: Chronic kidney disease is a significant contributor to mortality and morbidity worldwide, and the number of people who require dialysis or transplantation continues to increase. People on dialysis are 15 times more likely to die than the general population. Dialysis is also costly, intrusive, and time-consuming and imposes an enormous burden on patients and their families. This escalating problem has spurred a proliferation of trials in dialysis, yet health and quality of life remain poor. The reasons for this are complex and varied but are attributable in part to problems in the design and reporting of studies, particularly outcome selection. Problems related to outcomes include use of unvalidated surrogates, outcomes of little or no relevance to patients, highly variable outcome selection limiting comparability across studies, and bias in reporting outcomes. The aim of the Standardised Outcomes in Nephrology-Haemodialysis (SONG-HD) study is to establish a core outcome set for haemodialysis trials, to improve the quality of reporting, and the relevance of trials conducted in people on haemodialysis. Methods/design: SONG-HD is a five-phase project that includes the following: a systematic review to identify outcomes that have been reported in haemodialysis systematic reviews and trials; nominal group technique with patients and caregivers to identify, rank, and describe reasons for their choices; qualitative stakeholder interviews with patients, caregivers, clinicians, researchers, and policy makers to elicit individual values and perspectives on outcomes for haemodialysis trials; a three-round Delphi survey with stakeholder groups to distil and generate a prioritised list of core outcomes; and a consensus workshop to establish a core outcome set for haemodialysis trials.
is the most common form of kidney replacement therapy. This study aimed to examine the use, avail... more is the most common form of kidney replacement therapy. This study aimed to examine the use, availability, accessibility, affordability, and quality of HD care worldwide.
Objective To determine the global capacity (availability, accessibility, quality, and affordabili... more Objective To determine the global capacity (availability, accessibility, quality, and affordability) to deliver kidney replacement therapy (dialysis and transplantation) and conservative kidney management. Design International cross sectional survey. Setting International Society of Nephrology (ISN) survey of 182 countries from July to September 2018. Participants Key stakeholders identified by ISN’s national and regional leaders. Main outcome measures Markers of national capacity to deliver core components of kidney replacement therapy and conservative kidney management. Results Responses were received from 160 (87.9%) of 182 countries, comprising 97.8% (7338.5 million of 7501.3 million) of the world’s population. A wide variation was found in capacity and structures for kidney replacement therapy and conservative kidney management—namely, funding mechanisms, health workforce, service delivery, and available technologies. Information on the prevalence of treated end stage kidney di...
American journal of kidney diseases : the official journal of the National Kidney Foundation, Jan 3, 2016
Evidence-informed decision making in clinical care and policy in nephrology is undermined by tria... more Evidence-informed decision making in clinical care and policy in nephrology is undermined by trials that selectively report a large number of heterogeneous outcomes, many of which are not patient centered. The Standardized Outcomes in Nephrology-Hemodialysis (SONG-HD) Initiative convened an international consensus workshop on November 7, 2015, to discuss the identification and implementation of a potential core outcome set for all trials in hemodialysis. The purpose of this article is to report qualitative analyses of the workshop discussions, describing the key aspects to consider when establishing core outcomes in trials involving patients on hemodialysis therapy. Key stakeholders including 8 patients/caregivers and 47 health professionals (nephrologists, policymakers, industry, and researchers) attended the workshop. Attendees suggested that identifying core outcomes required equitable stakeholder engagement to ensure relevance across patient populations, flexibility to consider ...
Introduction Background. It has been estimated that 30-50% of adult haemodialysis patients have m... more Introduction Background. It has been estimated that 30-50% of adult haemodialysis patients have moderate to severe Chronic dialysis is an established treatment for patients malnutrition. We have previously shown that estimawith end stage renal disease. The number of new tion of total body nitrogen, expressed as a nitrogen dialysis patients is increasing world wide. However, index (NI) by in vivo neutron activation analysis the life-expectancy of these patients is still lower than (IVNAA) is an accurate tool for estimating total body that of the general population [1]. Dialysis patients protein in dialysis patients. It is not clear whether the have an age-adjusted death ratio that is estimated to nitrogen index is predictive of mortality and morbidity be 4-5 times more than that of the general population. in dialysis patients. A considerable proportion of this high mortality in Methods. We studied the long-term predictive value of these patients can be explained by a high prevalence nutritional assessment by IVNAA and serum albumin of non-renal comorbid conditions such as diabetes on mortality and morbidity (including infection epismellitus and cardiovascular disease [2]. In recent years odes requiring hospital admission, ischaemic heart there has been a growing realization that malnutrition disease (IHD), cerebrovascular or peripheral vascular in dialysis patients may be associated with poor outdisease (PVD). Seventy-six chronic haemodialysis come. Most studies agree that the effect of malnutrition patients were initially studied between 1989 and 1991, on morbidity and mortality in dialysis patients is with a minimum follow-up of 5 years. The mean age substantial. However, most of these studies are retroof the patients was 48.3 years (range 21-76). Patients spective and cross-sectional with limited long-term were divided into two groups, group I, n=22, had a follow up [3,4]. Moreover, traditional methods of NI∏0.8 (NI∏0.8 represents protein malnutrition) and nutritional assessment lack reproducibility and are group II, n=54, had a NI>0.8. prone to patient and observer error. We have shown Results. Fifteen patients in group II died in the followpreviously that anthropometry underestimates body up period compared to nine from group I (P<0.05), protein in haemodialysis patients and in vivo neutron but NI∏0.8 did not predict vascular or infective moractivation analysis (IVNAA) of total body nitrogen bidity. Serum albumin∏35 g/day did predict over all (TBN) is more accurate in the estimation of the mortality (P<0.05) as well as infection episodes nutritional state [5]. This study was designed to assess (P<0.001). When patients above the age of 50 years the predictive value of serum albumin, and total body were analysed, NI did predict mortality (P<0.05) but nitrogen by IVNAA on the long-term morbidity and serum albumin did not, while the age of>50 itself was mortality in haemodialysis patients. a strong predictor of mortality (P<0.001). Conclusion. We conclude that NI∏0.8 is predictive of long-term mortality. This reinforces the view that low body protein stores are predictive of increased mortal-Subjects and methods ity in dialysis patients and that the serum albumin is predictive of mortality because of its reflection of The study was approved by the Human Ethics Committee protein stores. of Monash Medical Centre. Ninety-one patients on haemodialysis between 1989 and 1991 under the supervision of
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Papers by Peter Kerr